1. Field of the Invention
The present invention relates to a novel cyclosporine composition in the form of an emulsion with a content of medium chain triglycerides. The emulsion is an oil-in-water emulsion, is bioequivalent to the marketed product SANDIMMUNE® but has an improved tolerability profile compared with SANDIMMUNE®.
2. Background of the Invention
Cyclosporine is a widely used immunosuppressant in organ and tissue transplantation. Cyclosporine has poor solubility in water, and a marketed product SANDIMMUNE® for infusion has been formulated as a concentrate containing 50 mg/ml cyclosporine and polyoxylated castor oil (CREMOPHOR EL®) in ethanol and must be diluted with an isotonic solution of sodium chloride or a 5% solution of glucose before administration. However, intravenous administration of cyclosporine composition containing CREMOPHOR EL® has been associated with hypersensitivity reactions, with responses ranging from mild skin reactions to anaphylaxis and cardiac collapse. Thus, there is a need for CREMOPHOR®-free cyclosporine compositions as well as ready-to-use compositions.
CREMOPHOR EL® is the registered trademark of BASF Corp. for its version of polyethoxylated castor oil. It is prepared by reacting 35 moles of ethylene oxide with each mole of castor oil. The resulting product is a mixture (CAS number 61791-12-6): the major 4846-7352-0668.1 component is the material in which the hydroxyl groups of the castor oil triglyceride have ethoxylated with ethylene oxide to form polyethylene glycol ethers. Minor components are the polyethylene glycol esters of ricinoleic acid, polyethylene glycols and polyethylene glycol ethers of glycerol. Cremophor EL is a synthetic, nonionic surfactant. Its utility comes from its ability to stabilize emulsions of nonpolar materials in aqueous systems.
A number of Cremophor products are available from BASF (Cremophor RH 40 (polyoxyl-40 hydrogenated castor oil), Cremophor EL (polyoxyl-35 castor oil), Cremophor ELP (extra pure grade of EL), which all are grades of polyoxyl castor oil, and Cremophor A 6 (macrogol-6-cetostearyl ether) and Cremophor A 25 (macrogol-25-cetostearyl ether), which are grades of macrogol cetostearyl ethers. To the best of our knowledge, at present only CREMOPHOR EL® has been associated with hypersensitivity reactions. However, it is likely that all the CREMOPHOR® products from the polyoxyl castor oil series have the same side-effect when administered to a subject.